Human kallikrein gene delivery attenuates hypertension, cardiac hypertrophy, and renal injury in Dahl salt-sensitive rats.
The tissue kallikrein-kinin system has been documented to be involved in the pathogenesis of hypertension and renal diseases. To investigate the protective effects of kallikrein gene delivery on salt-induced renal damage, cardiac dysfunction, and hypertension, adenovirus harboring the human tissue kallikrein gene under the control of the cytomegalovirus promoter Ad.CMV-cHK was delivered into Dahl salt-sensitive (Dahl-SS) rats fed to a high-salt (4% NaCl) diet. A single intravenous injection of Ad.CMV-cHK resulted in a significant reduction of blood pressure beginning 2 days post injection and the effect lasted for 4 weeks. The human kallikrein mRNA was detected in rat heart, kidney, lung, liver, and adrenal gland; immunoreactive human kallikrein can be measured in the liver, kidney, sera, and urine of rats receiving kallikrein gene delivery. Following Ad.CMV-cHK injection, a significant increase in urine excretion, urinary sodium output, kinin, and cGMP level was observed. Kallikrein gene delivery caused a significant reduction in the left ventricular mass and cardiomyocyte size as well as inhibition of glomerular sclerotic lesions and tubular dilatation. This study shows that adenovirus-mediated gene delivery in Dahl-SS rats fed a high-salt diet resulted in (i) prolonged reduction of blood pressure and increased urinary kinin and cGMP levels, consistent with blood pressure reductions mediated via kinin through a cGMP-dependent signal transduction pathway, (ii) inhibition of cardiac hypertrophy, and (iii) attenuation of renal injury. The ability of kallikrein gene transfer to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating salt-related hypertension as well as cardiovascular and renal diseases.
Chao
J
J
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425-2211, USA.
Zhang
J J
JJ
Lin
K F
KF
Chao
L
L
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000473:pathology / Q000628:therapy*; D003587:Cytomegalovirus / Q000235:genetics; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000628:therapy*; D007610:Kallikreins / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D051437:Renal Insufficiency / Q000473:pathology / Q000628:therapy*; D013997:Time Factors
D007610:Kallikreins